Method for preparing crystalline cephalosporin derivative

ABSTRACT

The invention provides crystalline (6R, 7R)-7-[[2-(2-Amino-4-thiazolyl)-(Z)-2-(1-diphenylmethoxycarbonyl-1-methylethoxy)imino ]acetamido]-3-(1-pyridiniummethyl)-3-cephem-4-carboxylate and a process for its production.

The present invention provides a new crystalline, highly pure and stable form of the syn-isomer of the cephalosporin derivative of formula ##STR1## as well as a process for its production.

The cephalosporin derivative of formula I is useful as an intermediate for the production of highly active cephalosporin antibiotics which can be administered parenterally and show a very broad spectrum of activity against pathogenic microorganisms, particularly in the gram negative area.

The syn-isomer compound of formula I has usually been isolated in the form of a salt, such as the dihydrochloride or chloride hydrochloride. Hitherto, the free betaine form has only been isolated from complex solvent mistures which has resulted in a product, in particular a solvate, with less than optimal purity and stability. It has now surprisingly been found that the syn-isomer of the compound of formula I can be isolated in free betaine form, and free of acid or solvent adducts, in excellent yield and purity (≧97%) as a stable highly crystalline product, direct from the reaction mixture used to produce it. The product has the physical characteristics set out in the Example hereinafter.

The present invention provides more particularly a process for the production of the syn-isomer of compound of formula I in crystalline form, comprising reacting the syn-isomer of a compound of formula II and/or IIa ##STR2## in which ##STR3## signify a 5- or 6-membered heterocyclic ring which may contain in addition to the nitrogen atom one or two further hetero atoms for example oxygen, nitrogen or sulphor, and which may be substituted, and which may be fused to a benzene ring which may itself be substituted, with a compound of formula III, ##STR4## in which R is hydrogen or an amino protecting group, or a salt thereof, e.g. the hydrochloride, mixing the resulting reaction mixture with a mixture of an acetic acid ester and a lower alkanol at a temperature of from 0° to 40° C., preferably 15° to 25°, and recovering the precipitated product. In this manner, the product crystallises out in a matter of a few minutes to a few hours in practically quantitative yield and high purity (≧97% yield and purity). Preferred acetic acid esters include C₁₋₆ alkyl acetates, preferably ethyl, propyl and butyl acetate. Preferred lower alkanols include ethanol and particularly, methanol. The ratio of acetate to lower alkanol to reaction mixture depends on the chosen acetate and alkanol but is usually about 2-3:1:1 by volume, particularly in the case of ethyl or butylacetate and methanol.

The nature of the "Het" ring in the compounds II and IIa is not critical, the preferred compounds being determined by such factors as availability of starting materials and ease of production. The preferred rings are 2-pyridyl and, in particular 2-benzylthiazolyl or less preferably pyrimidinyl, triazolyl or thiazolyl, and the corresponding thiones as in compounds IIa.

The compounds of formula II, IIa and III are known and may be produced in conventional manner.

In the following Example, which illustrates the invention of all temperatures are in °C.

Example: (6R, 7R)-7-[[2-(2-Amino-4-thiazolyl)-(Z)-2-(1-diphenylmethoxycarbonyl-1-methylethoxy)imino]acetamido]-3-(1pyridiniummethyl)-3-cephem-4-carboxylate

212 g of 2-(2-Amino-4-thiazolyl)-(Z)-2-(1-diphenylmethoxycarbonyl-1-methylethoxy)iminoacetic acid are suspended together with 138 g of triphenylphosphine in 800 ml of methylene dichloride, the mixture is cooled to 0° and 175 g of mercaptobenzthiazole disulphide are added. After 2 hours stirring at 0°, the formation of the thioester II or the corresponding compound IIa is complete (as determined by DC) and 260 g of 7-amino-3-pyridiniummethylcephalosporanic acid hydrochloride and 61 g of triethylamine are added at 0°. The mixture is stirred for 15 hours at 0° until the reaction is complete (as determined by HPLC) and the reaction mixture (yellow-brown) (ca. 1400 ml) is introduced into a mixture of 1400 ml of methanol and 3.5 liters of butylacetate at about 20°. The resulting clear solution is stirred at room temperature for 2 hours and then at 0° for a further 2 hours. The resulting highly crystalline precipitate is filtered off, washed with cold methanol and dried in vacuo. The highly pure (≧97%) by weight, free-flowing heading compound results. 

What is claimed is:
 1. A process for the production of crystalline (6R, 7R)-7-2-(2-Amino-4-thiazolyl)-(Z)-2-(1-diphenyl-methoxycarbonyl-1-methylethoxy) imino acetamido-3 (1-pyridiniummethyl)-3-cephem-4-carboxylate) comprising reacting a compound of formula II or IIa ##STR5## in which ##STR6## signify a 5- or 6-membered heterocyclic ring which may contain in addition to the nitrogen atom one or two further hetero atoms, and which may be substituted, and which may be fused to a benzene ring which may itself be substituted, with compound of formula III, ##STR7## in which R is hydrogen or an amino protecting group, or a salt thereof, and thereafter mixing the resulting reaction mixture with a mixture of an acetic acid ester and a lower alkanol at a temperature of from 0° to 40° C., recovering the precipitated product.
 2. A process according to claim 1, in which the acetic acid ester is ethyl, propyl or butylacetate.
 3. A process according to claim 1, in which the lower alkanol is methanol.
 4. A process according to claim 1, in which the ratio of acetate to alkanol to reaction mixture is 2 to 3:1:1 by volume.
 5. A process according to claim 1, in which the "Het" ring is 2-pyridyl or 2-benzylthiazolyl.
 6. A process according to claim 1, in which the reaction mixture, acetic acid ester and alkanol are mixed at a temperature of 15° to 25° C.
 7. The process of claim 1, in which 2-(2-amino-4-thiazolyl)-(Z)-2-(1-diphenylmethoxycarbonyl-1-methylethoxy)iminoacetic acid is reacted with mercaptobenzthiazole disulfide in methylene dichloride in the presence of triphenylphosphine and the resulting product is then reacted with 7-amino-3-pyridiniummethylcephalosporanic acid hydrochloride in the presence of triethylamine until the reaction is complete and thereafter mixing the resulting reaction mixture with butyl acetate and methanol at 0° to 20° to obtain highly crystalline (6R, 7R)-7-[[2-(2-amino-4-thiazolyl)-Z-2-(1-diphenylmethoxycarbonyl-1-methylethoxy)imino]acetamido]-3-(1-pyridiniummethyl)-3-cephem-4-carboxylate. 